CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Patients with one of the following diagnoses:

   1. Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma; OR
   2. Persistent or recurrent serous epithelial ovarian cancer
2. Progression or intolerance to at least one prior standard of care chemotherapy for advanced stage disease.
3. Subjects must have measurable disease as defined by RECIST 1.1 criteria.
4. Patients ≥ 18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Adequate organ and bone marrow function defined as:

   1. Hemoglobin ≥ 9 g/dL
   2. Platelets ≥ 75,000/µl
   3. PT/INR and PTT ≤ 1.5 x ULN
   4. Bilirubin ≤ 2.0 x ULN
   5. Creatinine ≤ 1.5 x ULN
   6. ALT/AST ≤ 5 x ULN (subjects with liver metastases) or ALT/AST ≤ 2.5 x ULN (subjects without liver metastases)
   7. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air
   8. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
7. Provides written informed consent.
8. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol

Exclusion Criteria:

1. Patients with known CNS metastases
2. Active invasive cancer other than the one of the two cancers targeted by this study. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder and prostate cancer with PSA level \< 1.0) are not excluded.
3. Active hepatitis B or hepatitis C infection.
4. Chronic hepatitis C with a FibroScan score equivalent to fibrosis stage 2 (F2) or greater.
5. Patients with known cirrhosis.
6. Patients with ongoing or active infection.
7. Patients with a known history of Li Fraumeni syndrome or retinoblastoma protein pathway germinal deficiency.
8. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
9. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (≤ 10mg equivalent of prednisone). Use of inhaled steroids is allowable.
10. Patients requiring supplemental oxygen therapy.
11. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
12. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heart Association Classification or other cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study. This determination will be made by a cardiologist if cardiac issues are suspected.
13. Pregnant or breastfeeding women.
14. RETIRED WITH PROTOCOL VERSION 5.
15. Patients with significant lung disease as follows:

    1. Patients with radiographic evidence of greater than lobar lymphangitic pulmonary involvement, greater than lobar bronchial wall thickening suggestive of peribronchial lymphatic disease extension, and/or evidence of extensive bilateral parenchymal metastatic burden.
    2. Patients with radiographic and/or clinical evidence of active radiation pneumonitis.
    3. Patients with radiographic evidence of underlying interstitial lung disease, including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy, targeted agents, amiodarone, nitrofurantoin, etc.)
16. Patients with prior/ongoing treatment that will not accommodate washout requirements for immune checkpoint inhibitors

主要终点：Type, frequency, severity, and attribution of AEs/SAEs as assessed by CTCAE v 5.0 · 2 years；Occurrence of dose-limiting toxicities. · 2 years；Recommended expansion dose of VCN-01 administered in combination with huCART-meso cells · highest VCN-01 dose at which 0 or 1 DLT occurs in 6 DLT-evaluable subjects · 42 days after Infusion #1 (huCART-meso cells or VCN-01 dependent on cohort assignment)；Occurrence of treatment-limiting toxicities (TLTs) · Number of subjects who either a) receive huCARTmeso cells and VCN-01 as per their arm assignment, or b) have a TLT qualifying event after receipt of either VCN-01 or huCART-meso cells. · 28 days after Infusion #1 (huCART-meso cells or VCN-01 dependent on arm assignment)；Comparison of the safety profiles of the two treatment arms via descriptive analysis · Up to 15 years post infusion
次要终点：Proportion of subjects enrolled who receive one or both of the intended study infusions；Overall Response Rate (ORR)；Best Overall Response (BOR)；Duration of Response (DOR)；Progression Free Survival (PFS)；Overall Survival (OS)

• Cohort 1 · EXPERIMENTAL · Single dose of 3.3x10(12) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
• Cohort 2 · EXPERIMENTAL · Single dose of 1x10(13) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
• Cohort -1 · EXPERIMENTAL · In the event that 2 DLTs occur in Cohort 1, then enrollment in Cohort 1 will be stopped and Cohort -1 will be opened for evaluation. Enrolled subjects will receive a single dose of huCART-meso cells on Day 0 followed by a single dose of 3.3x10(12) vp of VCN-01 on Day 14.
• Expansion Arm A · EXPERIMENTAL · Recommended expansion dose of VCN-01 as a single IV infusion on Day 0, followed by a single dose of 5x10\^7 huCART-meso cells on Day 7 (+3d) via IV infusion.
• Expansion Arm B · EXPERIMENTAL · Single dose of 5x10\^7 huCART-meso cells on Day 0 via IV infusion followed by the recommended expansion dose of VCN-01 as a single IV infusion on Day 7 (+3d).

This is a single-center phase 1 study to evaluate the safety and feasibility of huCART-meso cells given in combination with VCN-01 in patients with unresectable or metastatic pancreatic adenocarcinoma and serous epithelial ovarian cancer.